Human CRTH2 (chemoattractant receptor-homologous molecule on Th2 cells) is a seven transmembrane type G protein-coupled receptor (hereinafter, referred to as GPCR) that is also known as the aliases of GPR44, CD294, DP2, and the like. Further, it is known that human CRTH2 is one of receptors of prostaglandin D2 (hereinafter, referred to as PGD2) (Non-Patent Document 1). It is disclosed that CRTH2 was cloned as human Th2-specific protein in 1996 and referred to as B19 (Patent Document 1).
It is known that CRTH2 binds to PGD2 and PGD2 metabolites typified by 13, 14-dihydro-15-keto prostaglandin D2 (hereinafter, referred to as DKPGD2) which are ligands, transmits a Gαi protein-mediated signal into cells, and accordingly, is involved in migration and activation of CRTH2-expressing cells (Non-Patent Document 1).
Human CRTH2 is recognized to be expressed on Th2 cells, eosinophils, basophils, type 2 innate lymphoid cells (hereinafter, referred to as ILC2), or the like (Non-Patent Documents 1 and 2). It is reported that CRTH2 is a surface marker specifically expressed on Th2 cytokine-producing cells (Non-Patent Document 3).
Moreover, ILC2 is a novel cell population involved in allergic responses identified in humans in 2011 and CRTH2 is exemplified as a specific surface marker defining the cells (Non-Patent Document 2). Further, it is reported that CRTH2 is expressed on non-classical monocyte or Th2/Th17 cells (Non-Patent Documents 4 and 5).
In allergic diseases including asthma, it is known that CRTH2-expressing cells contribute to the pathology. It is reported that CRTH2-positive T-cells are recognized at a higher frequency in cells in bronchoalveolar lavage fluid of asthma patients than in cells of the healthy people (Non-Patent Document 6) and CRTH2-positive T-cells increase in correlation with the severity of atopic dermatitis (Non-Patent Document 7).
Since eosinophils contain granule protein having cellular cytotoxicity and deposition of the protein is found in respiratory tract tissues of chronic bronchial asthma patients or lesions of atopic dermatitis patients, it is considered that eosinophils play an important role in pathogenesis of allergic diseases such as chronic bronchial asthma or atopic dermatitis (Non-Patent Documents 8 and 9).
Basophils are involved in induction of an allergic reaction by storing inflammatory molecules such as histamine and leukotriene in cells and releasing them by crosslinking an Fcε receptor or an Fcγ receptor that is expressed on the cell surface to release the molecules (Non-Patent Document 10).
ILC2 is a cell present in a local area such as respiratory tract mucosa or skin. It has characteristics of producing a large amount of Th2 cytokines in response to cytokines such as interleukin (hereinafter, referred to as IL)-25 and IL-33 produced due to tissue injury, and is considered to be involved in pathogenesis of allergic diseases (Non-Patent Document 11).
As monoclonal antibody against CRTH2, 301108 (R&D) is commercially available. Further, BM16 is also known (Patent Document 2). These are rodent antibodies and have not been developed as medicine.
Moreover, it is also disclosed that a recombinant chimeric antibody and a humanized antibody regarding clone 19A2 remove CRTH2-expressing cells by effector activity and a humanized antibody regarding clone 8B1 and mouse antibodies regarding clones 3C12 and 31A5 have antagonist activity against CRTH2.
Further, it is disclosed that an antibody regarding clone 19A2 has reactivity to human mast cells (Patent Document 3).